JPH02167248A - Intermediate for producing carbacyclin - Google Patents

Abstract

NEW MATERIAL: Compounds of formula I [R₁₈ is O-R₁₀ (R₁₀ is protective group such as tetrahydropyranyl, etc.); R₂₀-R₂₄ are each H, R₂₄ is α-H or β-H; R₃₃ is CHO; X₁ is COOR₁ (R₁ is 1-12C alkyl): Z₄ is CH₂] or their salts.

USE: Intermediate for the synthesis of novel carbacyclin analogues of formula II [R₇ is (CH₂)_m-CH₂ ((m) is 1-5); R₈ is OH; M₁ is α-OH: β-OH; Y₁ is trans or cis CH=CH] useful as antithbromogenic agent, antiulcer agent, and antiasthma drug.

PROCESS: For example, a compound is decomposed with ozone to obtain a compound of formula I. The obtained compound is reacted with an appropriate Wittig reagent, reduced and hydrolyzed to obtain a compound of formula II.

COPYRIGHT: (C)1990,JPO

Description

[Detailed description of the invention] [Not for industrial use! l'F 1 The present invention provides novel chemical intermediates.

The present invention particularly relates to intermediates of carbacyclin analogues that are modified at the C-5 or C-9 position, in particular novel derivatives of prostacyclin or PGT.

Prostacyclin is a compound produced endogenously in mammalian species and is related biosynthetically to ten staglandins (PG'S). When particularly unsaturated at the C-5,6 position, prostacyclin exhibits the structure and carbon atomic number of Formula 1.

1 Historically, prostacyclin is often simply RPGI2J
It is expressed as Carbacycline, i.e. 6a-carba-
P], when the C-5,6 position is unsaturated, represents the structure and carbon atomic number shown in formula ■.Similarly, Rubacycline is simply referred to as r CBlh J. .

A stable partially saturated derivative of PCI2 is PCI, i.e. when the C-5,6 position is saturated, the C-5°6 position, depicted by the carbon atomic number in formula Sometimes 5, 6. -dihydro-PGT, the corresponding 5,6-dihydro〇A is CBA drawn by the formula ■
, there is.

As is clear from a consideration of Formulas I and 2, prostacyclin and carbacyclin are PGF-type compounds.

Eventually, PGF of the formula (■) is commonly known as a derivative of α. Therefore, prostacyclin is commonly referred to as 9-deoxy-6,9α-epoxy-(5Z)5,6-sibuhydro-PGFr, and carbacyclin is
-deoxy-6,9α-methane-<5E)-5,6-didehydrol-PGF, an article on prostacyclin and its structural identification is given by digocison (Jo
hnson) and other grosstaglandins (Prosta
grantlins) Volume 12, Page 915 (1976)
Please refer to

For convenience, this novel glostacyclin is a carbacycline analogue with J, He
d, Chel, Vol. 17, p. 911 (197, 1).

All novel prostacyclin derivatives herein will be according to the common and technically accepted nomenclature system described by A. Nelzin (N, A, Nf318On). It will be named as deoxy-PGF, - type compounds, PGI□jA conductors, or preferably as CBA, or CBA=Rj4 conductors.

In the formulas herein, a dashed bond to a ring represents a substituent that is in the alpha (α) configuration, i.e., below the plane of the ring;
A thick solid line bond to a ring indicates a beta (β) configuration, i.e., a substituent on the upper side of the ring; in this MA, a wavy line (~)
The use of would represent attachment of the substituted JA group in the alpha or beta configuration, or in a mixed alpha and beta configuration. Instead, the wavy line is E
Z may represent any of the isomeric configurations or mixtures thereof.

The chain measuring hydroxyl at C-15 in the formula of this specification is:
Cahn-Ingoldorff log ranking rule (Cahn-1)
111JO1(U-Prelogseauencer
ules) (J.

in the S and R configurations as defined by Chera, Ed. 41, p. 16 (1964). Nature (N
a-ture) Vol. 212, p. 3 (1966). This discussion applies to the novel prostacyclin and carbacyclin analogs of the present invention. Prostacyclin and carbacycline molecules each have several asymmetric centers and therefore can exist in either an optically inactive form or in two enantiomeric forms (optically active), i.e. dextrorotatory or levorotatory. The formula of PGT, as shown, corresponds to PCI2, which is produced endogenously in clear mammalian species. In particular, endogenously produced prostacyclin,
C-8 (α), C-9 (α), C-11 (α) and C-
Note the stereochemical configuration in 12(β), the mirror image of the above formula for prostacyclin represents the enantiomers of the composition; the racemic form of prostacyclin honors the same number of molecules of both enantiomers.

For convenience, references to stacycline and carbacycline will be to their optically active forms. As mentioned above, with respect to prostacyclin, reference is made to its type having the same absolute configuration as that obtained from species A.

The term "prostacyclin-type" product as used herein relates to any cyclopentane derivative of the invention that is useful for at least one of the same pharmaceutical purposes for which prostacyclin is used.

The formulas depicted herein that depict 10 stacyclin-type products or intermediates useful in their preparation are prostacyclin-type products that are in the same relative stereochemical configuration as the prostacyclin obtained from the open-pore series 4fl&1. Represents a particular stereoisomer of a cyclin-type product or of an intermediate useful in making a stereoisomer of the prostacyclin-type products described above.

The term "prostacyclin analogue" or "carbacyclin analogue" refers to a stereoisomer, or stereoisomer of a stacycline-type product that is of the same relative stereochemical configuration as stacycline obtained from mammalian M. The term "stacycline analogue" or "carbacycline analogue" refers to a mixture consisting of a prostacyclin-type product and its enantiomers, particularly when formulas are used herein to depict prostacyclin-type products. Refers to a compound of the formula or a mixture consisting of the compound and its enantiomer.

[Prior art] Carbacyclines and closely related compounds are known in this technology, as disclosed in Japanese Patent Publication Nos. 63,059 and 6.
No. 3,060 (also respectively Downend Farm Dock CP! No. 18154 B, '2G and 48155
See also British Publication No. 2,012,265 and German Publication No. 2,900, abstracted as Derwent Firm CP1 No. 54825 B, /'30. See also U.K. flJ filed application 2,017,6
99, 2.014143 and 2.013,661 et al.

The synthesis of carbacyclines and related compounds has also been reported in the chemical literature as described below. Horton D, R, et al., Journal of Organic Chemistry (J.

Organic chelstry) Volume 44, 28
80 pages (1979), Shibasaki M, (Sh
ibasaki H, etc., Tetrahedron Letters, 4
pp. 33-436 (1979): Kojima Gay, (
KOjilaK,) etc., Tetrahedron Letters,
3743-3746 (1978): Nicolaou Kay,
(NiC01aOtlK, C,) et al., Journal of the Gemiconductor Society, Gemmical Communications (J.

Chen、Soc、、Chemical Co1nu
nications) pages 1067-1068 (197
8); Sugie^, etc., Tetrahedron Letters, pp. 2607-2610 (197
9th year); Shibasaki M, Chemistry Letters (Ch.
elistry Lettera) 1299-13
00 pages (1979) and Hayashi M.
ashi H,), Chell.

Lett, 1437 p. 40 (1979), and (
Li), Tsunq-tee
Facile synthesis of r9(0)-methano-prostacyclin (A Facile 5ynt-heS:S or
9(Q) Hethano Pr03jaCV
C1! n) J, abstract number 378 (organic chemistry) and P, A, Aristoff (P, A, ^ristoff)
r 6 a-Carbaprostacycry>1=(1) Synthesis of 6 a-Carba
Pros-tacyclin L) J, Abstract No. 236 (Organic Chemistry), both published August 24-29, 1980
The Second Congress of the North American Conference was held in San Francisco (Las Vegas, Nevada), California, United States of America.
orth Anerican Continent)
Published in the paper abstract (Part ■).

7-oxo and 7-hydroxy-CBA, compounds are
No. 4,192,891. 19-hydroxy-CBA-, the compounds are 1
United States Application No. 05.1, filed July 5, 979,
811. Aromatic esters of CBA2 are disclosed in US Pat. No. 4,180,657.

11-deoxy-Δ10- or Δ”-CBA, compounds are disclosed in Japanese Patent Publication No. 77/'24,865 (published February 24, 1979).

[Means for solving the problem] Box A11l is particularly suitable for producing formula XI,
Carbacycline intermediates of Formula VI are provided.

In this formula, R3 is α-011:β-■[, R7 is -(Ctl□), -C11s (m is 1 to
(an integer of 5) and 艮? 1JhH口Nshitewa°), R
18 is hydrogen, hydroxy, hydroxymethyl, -on,
, (here RIQ is a protecting group such as tetrahydropyranyl)
, R20, R21, R2□, R23 and R24 are all hydrogen, R22 is either α-hydrogen or β-hydrogen, and in formula XI, Lo, R23, R24 are hydrogen and R2
1 and R1 together form a second valence bond between t:c-9 and C-6a, 833 is 10;
Cl2) alkyl, V, is trans-CI=Cl1- or cis-CII
= Ct(-, and 14 is -C11□-.

[Nomenclature 1 Regarding the above divalent substituents (symbols) (1'! II, Ll and 141), these divalent groups are α-R3; β-
R, is defined. This old one is C-8~C12 cyclo10
R4 represents a substituent of the divalent moiety in the alpha configuration with respect to the plane of the pan ring, and R4 represents a substituent of the divalent moiety in the beta configuration with respect to the plane of the ring 6 Therefore, H,
-0]1: When defined as β-R5, the hydroxy of the H2 moiety is in the alpha configuration, ie, ρGl, above.

The Rs substituent is in the beta configuration.

The carbon atom number of various hydrocarbon-containing moieties is referred to by a prefix denoting the lowest and highest number of carbon atoms in the moiety, i.e. the prefix (CC4) is an integer i to an integer j carbon. Refers to the part of an atom.

Thus, (C,-C3)alkyl refers to alkyl of 1\3 carbon atoms, ie methyl, ethyl, propyl and isopropyl.

Compounds IIXI are PGE or PG as described below.
F+ derivatives are designated as derivatives.

CBA analogs of formula XI where R2゜, R2, , R2□, R23 and R24 are all hydrogen and R22 is β-hydrogen are “9-deoxy-2゛,9α-methano-3-oxa-4 ,5,6-trinor-3,7-(1°,3゛-interphenylene) PGF+ is characterized as a J compound. 9β-methano-3-oxa-4,5,6-trinor-3,7-(1′,3′-interphenylene)-PGF,” compounds. CB analogs in which R2o, R23 and R24 are all hydrogen and R21 and R22 together form a valence bond between C-9 and C-6a are "9-deoxy-2", 9 -methano-3-oxo-3
, 4,5hlinol-3,7(1',3-interphenylene) PGF+ J1 is characterized as a compound.

Compounds in which Yl is cis-CH=C11- and the H+ moiety contains hydrokiccyl in the α-configuration are named "15-ebi-〇B^" compounds.

Statement number for this convention of nomenclature for defining C-15 epimers, as of April 5, 1977.
Ilvt Patent No. 4.016.184, especially 24-27
Please refer to m.

-(Cl1□)1-, cis-CH=C1 as Y3 moiety
The novel carbacycline analogues which can be derived from the intermediates of the present invention, containing N3,14-, are therefore N3,14-
They are called ``didoro'' and ``cis-13'' compounds.

m is as defined above, R7 is a linear -(CL
), -CH3, then the compound so described i is m
is 1.2.4 or 5, respectively r19,20-dinor", "20-nor", "20-methyl" or "20
-ethyl”.

When at least ta of R3 and R1 is not hydrogen, rIG, 16-difluoro'' (R1 and R
(4 is both fluoro) compounds are described.

Furthermore, when N1 is -COOR, the novel parent compounds of this specification 3 can be named as CBA-type esters or CBA-type salts.

Examples of alkyl of 1 to 12 carbon atoms are methyl, ethyl, propyl, butyl, pentyl, hexyl, hegetyl, octyl, nonyl5decyl, undecyl, dodecyl,
are their isomeric forms.

Effects of the Invention The novel CB8 analogues prepared from the intermediates of the invention disclosed in Box 4III produce certain prostacyclin-like pharmacological responses.

The novel 2X I CBA analogues are therefore useful for the treatment of diseases and ponds in mammals, especially humans, valuable livestock, companion animals, zoological specimens, and laboratory animals (e.g., sharks, rats, rabbits, and monkeys). Research, prevention of undesirable physiological conditions,
Used as a drug in control and treatment. Among other things, these compounds can be used as antithrombotic agents, anti-a
It has useful applications as a tumor agent and anti-inflammatory drug.

(a) Inhibition of Platelet Aggregation These novel CBA analogs disclosed herein are useful at any time for inhibiting platelet aggregation, reducing platelet adhesion, or removing or preventing the formation of blood clots in human-bearing mammals. be. These compounds may then be used in the treatment and prevention of myocardial infarction, in the treatment and prevention of postoperative thrombosis, in promoting the patency of graft vessels after surgery, in the treatment of peripheral vascular disease, and in the treatment and prevention of atheromatous arteries. Useful in the treatment of conditions such as sclerosis, arteriosclerosis, hypocoagulability due to lipemia, and other clinical conditions where the underlying etiology is combined with lipid imbalance or crystallipemia. It is. Other in vivo applications include the prevention of cerebral ischemic attacks and long-term care following myocardial infarction and stroke; for these purposes, the compounds may be administered systemically, including intravenously, subcutaneously, and intramuscularly. For long-term effects, it is administered in the form of sterile implants. Because of the rapid response, the intravenous route of administration is preferred, especially in emergency situations. Dosages ranging from about 0.01 to about 10 μg/kg body weight per day may be used, with the correct dosage depending on the age, weight, condition, and frequency and route of administration of the patient or individual.

The preferred administration of these compounds is oral, but other non-parenteral routes (e.g. buccal, rectal, sublingual)
are also used rather than the parenteral route. Oral dosage forms are conveniently formulated into tablets, capsules, etc. and administered two to four times per day.

Doses in the range of about 0.05 to 1 oo square centimeter per body weight per day are effective.

Addition of these compounds to whole blood provides in vitro applications such as storage of whole blood for use in heart-lung machines. Additionally, whole blood containing these compounds can be circulated through organs from which it has been removed prior to transplantation, such as the heart or kidneys. They are also useful in making platelet-rich concentrates for use in the treatment of thrombocytopenia, chemotherapy, and radiation therapy. For in vitro applications, doses of 0.001 to 1.0 microns per ml of whole blood are used. United States Patent No. 4,103,02 for the treatment of peripheral vascular disease
Please refer to 6.

fb) Reduction of gastric juice secretion The novel CBA analogs disclosed herein also reduce and suppress gastric juice secretion, thereby reducing or avoiding the formation of gastrointestinal ulcers and also reducing the number of ulcers already present in the gastrointestinal tract. L:j
It is useful for humans and useful animals such as mammals such as dogs and pigs. For this purpose, these compounds may be used for about 0.1 μQ to about 20 μQ per kli of body weight per minute.
In the infusion dosage range of Q, or about 0 per kg body weight per day
．． The total daily dose by injection or infusion ranges from 0.01 to about 10.0 cm, administered intravenously, subcutaneously or intramuscularly, but the exact dose depends on the age, weight and condition of the patient or animal and the administration. Depends on the number of times and route.

Preferably, however, these new compounds are administered orally or by a non-parenteral route.

When used orally, a dosage range of about 1.0 to 100 cm per body weight per day, administered 1 to 6 times per day, is used.-Once healing of the ulcer is achieved; The maintenance doses required to avoid relapse are as long as the patient or animal is asymptomatic.These novel CBA analogs disclosed herein are derived from systemic administration of anti-inflammatory prostaglandin synthase inhibitors. It is also useful to reduce undesirable gastrointestinal effects, and co-administration of prostaglandin derivatives and anti-inflammatory prostaglandin synthase inhibitors is useful for this purpose. For the disclosure that the ulcerative consequences induced by non-steroidal anti-inflammatory abrasions of the species are inhibited by the simultaneous oral administration of prostaglandins, see Partridae et al., U.S. Pat. 78
1,429, these novel CBA analogs herein are therefore useful in reducing undesirable gastrointestinal effects from systemic administration of, for example, indomethacin, phenylbutacin, and aspirin. It is. These are the substances specifically mentioned as non-steroidal anti-inflammatory agents in the disclosure of Bartridge et al. They are also known to be prostaglandin synthase inhibitors.

The anti-inflammatory synthetase inhibitor, such as indomethacin, aspirin or phenylbutacin, may be administered by any method known in the art to alleviate inflammatory conditions, including any ingestion dosage and any known route of systemic administration. .

(d) Bronchodilator (anti-11i) These novel analogues disclosed herein are also useful in the treatment of asthma.6 For example, these compounds may be used as bronchodilators or as antigen-antibody complexes. It is useful as an inhibitor of bronchial stenosis induced by mediators such as 5R8-A and histamine released from cells activated by 5R8-A.

Therefore, these compounds can suppress attacks during conditions such as bronchitis, bronchiectasis, bronchial pneumonia, and emphysema.
Makes breathing easier. For these purposes, these compounds can be administered in various administration forms, such as orally in the form of tablets, capsules or liquids, intrarectally in the form of a suppository, although in emergency cases intravenous administration is preferred, Orally, subcutaneously or intramuscularly,
Administered by inhalation method in the form of an aerosol or solution for a nebulizer, or by insufflation method in powder form, doses ranging from about 0.01 to 5 cm per kilogram of body weight are used 1 to 4 times a day. However, the exact dose will depend on the patient's age, weight, and symptoms as well as the frequency and route of administration. These CBAs are used for the above applications.
Analogs can be used with other anti-asthmatic drugs, such as sympathomimetics (isoproterenol, phenylephrine, ephedrine, etc.), xanthine derivatives (theophylline and aminophylline) and corticosteroids (octaCTI+ and prednisolone). Can be conveniently combined.

These compounds are effectively administered to human asthmatics by oral inhalation or by aerosol inhalation. For administration by the oral inhalation route using a common nebulizer or oxygen aerosolization method, the dilute solution preferably has a concentration of about 1 part of drug to form a total solution of about 100 to 200 parts by weight;
It is advantageous to supply the active ingredient. All common additives can be used to stabilize these solutions or to provide an isotonic medium, such as sodium chloride, sodium citrate, citric acid, sodium bisulfite, etc. Inhalation For administration as a self-propelled unit for administering the active ingredient in an aerosol form suitable for therapeutic use, the composition may be combined with an inert propellant, together with co-solvents such as ethanol, flavoring substances and stabilizers. The active ingredient can be suspended in an agent such as a mixed paste of dichlorodifluoromethane and dichlorotetrafluoroethane.

Suitable means for use in aerosol inhalation therapy techniques are fully described in open US Pat. No. 3,868,691.

When x1 is -GOOR+, the novel CB8 analogues so described can be used in the free acid form,
Used in ester form or pharmaceutically acceptable salt form. When the ester form is used, the ester is any of those within the above definition of R1. However, it is preferred that Nisder is alkyl of 1 to 12 carbon atoms. Among the alkyl esters, methyl and ethyl are the body or experimental behavior! Particularly suitable are the 1# systems for optimal absorption of the compounds, and the straight-chain octyl, nonyl, decyl, undecyl and dodecyl are particularly suitable for long-term activity.

Pharmaceutically acceptable salts of the novel prostaglandin analogues derived from the intermediates of the present invention for the above purpose include pharmaceutically acceptable metal cations, ammonia, amine cations, or quaternary ammonium cations. It is with cations.

Particularly suitable metal cations are those derived from alkali metals, such as lithium, sodium, and potassium, and supra-alkali metals, such as magnesium and calcium, but also from other metals, such as aluminum, zinc, and iron. Cationic forms of are also possible.

Pharmaceutically acceptable amine cations are those derived from primary, secondary, and tertiary amines. Examples of suitable amines are methylamine, dimethylamine, 1-lymethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, pendylamino,
Dibenzylamine, α-phenylethylamine, β-phenylethylamine, ethylenediamine, diethylenetriamine, adamantylamine and aliphatic, cycloaliphatic, araliphatic amines and heterocyclic amines containing up to about 18 carbon atoms, such as piperidine. , morpholine, pyrrolidine, piperazine and their lower alkyl derivatives, such as 1-methylpiperidine, 4-ethylmorpholine, 1-ingrovirpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, etc. Amines containing water-soluble or hydrophilic groups, such as mono- and triethanolamine, ethylgetanolamine, N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-
Ethyl-1,3-propanediol, 2-amino-2-
Methyl-l-gropanol, l-lis-(hydroxymethyl)aminomethane, N-phenylethanolamine,
N-<p-tertiary amyl phenyl) jetanolamine,
These include galactamine, N-methylpyridine, N-methyl-glucosamine, ephedrine, phenylephrine, epinephrine, and glopyrine. Additionally, basic amino acid salts such as lysine and arginine are also useful amine salts.

Examples of suitable pharmaceutically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium, and the like.

2-Decarboxy-2-aminomethyl- or 2-(1!substituted aminomethyl)-C provided by the present invention
Acid addition salts of BA analogs include hydrochloride, hydrobromide salts prepared by reacting CBA analogs with a stoichiometric amount of an acid corresponding to a pharmaceutically acceptable acid addition salt. , hydroiodide, sulfate, phosphate, cyclohexane sulfamate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, etc.

Certain compounds are preferred to obtain an optimal combination of specificity, potency, and duration of activity of the biological response.

[Protecting Groups] Protecting groups within the Lo range replace hydroxy hydrogens and are not as attacked or reactive as hydroxys by the reagents used in the transformations used herein, and are subsequently removed by prosthesis. Any group that can be substituted for hydrogen by acid hydrolysis in the production of grandin-type compounds.

Several such protecting groups are known in the art, such as tetrahydropyranyl and substituted tetrahydropyranyl. For reference, E.J.
．． Ccrey) of rProceedinga of
theRobert A. Welch Foundation
ion Conferences onChenica
l Research,XIIOr(fanIC S
ysthesis J, pp. 51-79 (1969). Protecting groups that have been found to be useful include: (a) tetrahydropyranyl, (b) tetrahydrofuranyl, (c) formula -C(ORI+)(R,ffi)- Cll(
It,3) (R,,) group [where Rz is alkyl having 1 to 18 carbon atoms, cycloalkyl having 3 to 10 carbon atoms, aralkyl having 7 to 12 carbon atoms, phenyl, or RI2 and Ro are alkyl having 1 to L1 carbon atoms, substituted with 1 to 3 phenyl, and RI2 and Ro are alkyl having 1 to 4 carbon atoms, phenyl, phenyl having 1 carbon atom,
phenyl substituted with 1.2 or 3 of ~.1 alkyl, or R12 and R15 when taken together are -(CL), -, or R
, 2 and R1 when taken together -(Cll:
) b −0−(Cll4 > e−, where a
is 3.4 or 5, b is 1.2 or 3, and C is 1.2 or 3, provided that b+c is 2.3 or 4, and further conditions as
and ft1) silyl groups according to R2s as defined below.

[When one group R10 is tetrahydropyranyl,
The tetrahydropyranyl ether derivative of any hydroxy moiety of the CBA-type intermediates herein is prepared in an inert solvent such as dichloromethane in the presence of an acid condensing agent such as p-toluenesulfonic acid or pyridine hydrochloride. is obtained by reacting a hydroxy-containing compound with 2,3-dihydropyran.

The dihydrobilane is used in large stoichiometric excess, preferably in an amount of 4 to 100 times the stoichiometric amount.

The reaction is usually complete within 1 hour at 20-50°C.

When the protecting group is tetrahydrofuranyl, 2,3-dihydrobyran is replaced by 2, as described in the previous section.
．． 3-dihydrofuran is used.

The eA protecting group has the formula -〇(ORz)(It+2)-C1l(R
+i) (R+4) [wherein R11, R12, Ro and R
When 14 is as defined above, it is a vinyl ether or an unsaturated cyclic or heterocyclic compound, such as IPJ, 1-cyclohexene-1-
yl methyl ether or 5,6-sihydro-4-methoxy-2H-pyran. C.B. Leeds (
J, Anerican (C, B, Reese) et al.
Chen+caSociety 89.3366 (1
(967), the reaction conditions for such vinyl ether necks and unsaturated compounds are similar to those for dihydropyran described above.

R28 is a silyl protecting group of formula -3i(G+)s.

In some cases, silylation methods in which all hydroxyls of the molecule are silylated are common, but in the case of songs, one or more hydroxyls are silylated and at least one other hydroxyl is silylated. hydroxyl of )XJ8'
It is a selective thing that remains untreated. For any of these silylations, -3ifG+)
Silyl groups within the scope of s include trimethylsilyl, dimethylphenylsilyl, tonophenylsilyl, tert-butyldimethylsilyl, or methylphenylbenzylsilyl.

For G, examples of alkyl are methyl, ethyl, globyl, isobutyl, butyl, nibutyl, tertiary butyl,
Such as vesitil. Aralkyls include besidyl, phenethyl, α-phenylethyl, 3-phenylpropyl, α-naphthylmethyl and 2-(α-naphthyl)ethyl. Examples of phenyl substituted with halogen or alkyl are p-chlorophenyl, m-fluorophenyl, o
-tolyl, 2.4-dichlorophenyl, p-tertiary methylphenyl, 4-chloro-2-methylphenyl, and 2.
4-dichloro-3-methylphenyl.

These silyl groups are well known in the art6, for example, as described in Pierce's “Silylation of Organic Compounds (Si
Lylation of Organic Compo
unds)'', Pierce Chemical Company, Rockfeed, IL, (1968). The use of silyl groups that are known to be resistant (one example being trimethylsilyl) should be avoided.

Furthermore, when it is desired to selectively introduce silyl groups, silylating agents that are readily available and known to be useful for selective silylation are used. For example, a tert-butyldimethylsilyl group is used when selective introduction is required. Furthermore, when attempting to selectively hydrolyze a silyl group in the presence of a cA protecting group or an acyl protecting group according to RIG, it is possible to use easily available and tetra-n
-A silyl group is used which is known to be easily hydrolysable using butylammonium fluoride.

A particularly useful silyl group for this purpose is tert-butyldimethylsilyl, whereas a silyl group (such as lhelimethylsilyl) is not used when selective introduction and/or hydrolysis is required. Protecting groups as defined by can be removed by other methods, such as (1) hydrochloric acid in methanol, (2) a mixture of acetic acid, water and tetrahydrofuran, or (3) in tetrahydrofuran. Hydrolysis of the protecting group is achieved by reaction with aqueous citric acid or aqueous phosphoric acid at temperatures below 55°C.

As mentioned above, Ll is a protecting group for hydroxy group hydrogen.

Ri+ may then be an acyl protecting group according to R, an acid hydrolyzable eA protecting group according to RIO, a silyl protecting group according to R211, or an arylmethyl group that replaces the hydroxy hydrogen according to R34.

Acyl protecting groups according to R include (a) benzoyl, (b) alkyl of 1 to 4 carbon atoms, or phenylalkyl of 7 to 12 carbon atoms, or nitro;
benzoyl substituted by 5, with the proviso that there are less than 2 substituents other than alkyl, and the total carbon atoms in the substituents does not exceed 10, and with the proviso that the substituents are the same or May be different.

(C) benzoyl substituted with alkoxycarbonyl having 2 to 5 carbon atoms; (0 naphthoyl); (e) alkyl having 1 to 4 carbon atoms;
10 phenylalkyl, su is nitro, 1 to 9 W-substituted naphthoyl, provided that there are less than 2 substituents other than alkyl on any fused aromatic ring;
and the total carbon atoms in the substituents on any fused aromatic ring does not exceed 10 (I!l), provided further that the various substituents are the same or different, or (f) carbon Included are alkanoyls of 2 to 12 atoms.

In the preparation of these acyl derivatives of hydroxy-containing compounds, methods generally known in the art are used. Thus, for example, a dehydrating agent such as p-toluenesulfonyl chloride or dicyclohexyl A carbodiimide is reacted with a hydroxy-containing compound in the presence of a carbodiimide, or alternatively an anhydride of an aromatic acid of formula (R9)011, such as an anhydride, is used.

However, it is preferably proceeded by the method C described in the previous section using a suitable acyl halide, such as R* 1laj [where 1181 is chloro, bromo, or iodo]. 6 Reactions with hydroxy-containing compounds in the presence of hydrogen scavengers, e.g. tertiary amines such as pyridine, triethylamine, etc., are carried out under a variety of conditions and using procedures commonly known in the art. . Generally mild conditions, i.e. 0-60°C, liquid media (excess pyridine or inert solvents, e.g. benzene,
Contacting the reactants in (toluene or chloroform) is used. Acylating agents are used in stoichiometric amounts or in substantially stoichiometric excess.

As an example of R9, the following compound is acid (R90+1), fR
*) 20, or acyl chloride (It, CJ
) can be used as: benzoyl; substituted benzoyl, (2-3-1 or 4-)methylbenzoyl,
(2-3-1 or 4-)ethylbenzoyl, (2-3-
2 or 4-)isopropylbenzoyl, (2-13-1
or 4-) tert-butylbenzoyl, 2,4-dimethylbenzoyl, 3.5-dimethylbenzoyl, 2-isopropyltolyl, 2,4.6-trimethylbenzoyl,
Pesitamethylbenzoyl, phenyl (2-3-1 or
1-) toluyl, (2-13-1 or 4-) phenethylbenzoyl, (2-3-1 or 4-) nitrobenzoyl, (2,4-12,5-1 or 2.3->dinitrobenzoyl, 2.3-dimethyl-2-nitrobenzoyl, 4
．． 5-dimethyl-2-nitrobenzoyl, 2-21-lo-6-phenylnitylbenzoyl, 3-nitro-2-phenethylbenzoyl; monoesterified phthaloyl, inphthaloyl, or terephthaloyl: l- or 2
-naphthoyl: substituted naphthoyl, e.g. (2-1
3-145-56-, su is 7-) Methyl-1-naphthoyl, (2- or 4-)ethyl-l-naphthoyl, 2-isopropyl-l-naphthoyl, 4,5-dimethyl-i-
naphthoyl, 6-yne 10bi-4-methyl-1-naphthoyl, 8-benzyl-1-naphthoyl, (3-54-
15-1 or 8-)nitro-1-def-1-yl, 4.5
-dinitro-1-naphthoyl, (3-14-16-17
-1 or 8-) methyl-1-naphthoyl, 4-ethyl-
2-naf I hale, and (5- or 8-)nitro-2-
naphthoyl and acetyl.

Therefore, benzyl chloride, 4-nitro-benzoyl chloride, 35-dinitrobenzoyl chloride or the like, ie Re CJ compounds corresponding to the R, groups mentioned above, can be used. If the acyl chloride is not available, it is prepared from the corresponding acid and phosphorus pentachloride as known in the art. Re Otl, (Re) 2
It is preferred that the 0 , or R,Cj reactants have no bulky sterically hindering substituents on both ring carbon atoms adjacent to the carbonyl attachment site, such as tert-butyl.

The acyl protecting group according to R9 is removed by deacylation. For this purpose, alkali metal carbonates or hydroxides are advantageously used at room temperature, such as potassium carbonate or hydroxide in aqueous methanol at about 25°C.

R34 can be substituted for an intermediate hydroxy hydrogen in the preparation of the various CBA analogs herein and then by hydrogen in the process of making these corresponding prostacyclin analogs, such that the R34-containing compound is It is defined as an arylmethyl group that is stable with respect to the various reactions it undergoes and that is introduced and subsequently removed by hydrolysis under conditions that result in substantially quantitative yields of the desired product. Ru.

Examples of arylmethyl groups substituting hydroxy-hydrogen are: (a) benzyl, (b) alkyl having 1 to L1 carbon atoms, chloro, bromo, iodo, fluoro, nitro, benzyl substituted by 1 to 5 of 7 to 12 7enylalkyl, provided that the various substituents are the same or different; (c) benzhydryl; (d) 1 to 5 carbon atoms; Benzhydryl substituted with 1 to 10 of 4 alkyl, chloro, bromo, iodo, fluoro, di-ro, phenylalkyl of 7 to 12 carbon atoms, provided that various substituents are substituted with each aromatic (e) trityl; (f) alkyl of 1 to 4 carbon atoms; chloro; bromo; iodo; fluoro; nitro; phenyl of 7 to 12 carbon atoms; Trityl substituted by 1 to 15 of alkyl, with the proviso that the various substituents are the same or different on each aromatic ring.

The introduction of such ether linkages into the hydroxy-containing compounds herein, in particular benzyl-substituted benzyl ethers, can be carried out by methods well known in the art, e.g. It is carried out by reaction with benzyl halide (chloride, bromide, or iodite). This reaction proceeds in the presence of a suitable condensing agent (eg silver oxide).

A reaction time of 4 to 20 hours, 69 times in which the mixture is stirred and heated to 50 to 80 DEG C., is sufficient.

Manufacturing Process The figures herein describe how the novel intermediates, classes and final products of the invention are manufactured by the novel process of the invention. Regarding these figures, b, H+, R7, R8
, R1゜, R15, Re6, R, a, RIM, R
2°, R21, R22, Li and R24, Ro, Ll
, xl, Y, and 24 are as defined above in a.
R37 is the same as R4□, except for -CI+ and 011. R3g is -0R31, hydrogen, or -CI□0
R31, where R1 is as defined above.

L□ is -(C1,), -C1+(011)-CH
, is-(C1h) 2-CIItOR,,)-C11
, is the same as R7. R17 is II7
Same as, but except for hydrogen. AC is acetyl.

CBA analogs of formula manufactured by the method. US Patent 4,1
No. 81,789, this compound can be prepared by methods well known in the art to obtain the corresponding methylene of formula ctxxn and c
It is conveniently converted to hydroxymethyl compounds of txxm. Such methods are particularly described in U.S. Pat.
7 and 4,060,534.

The compound of formula ctx x m thus prepared is then converted to the mesylate of CLXXIV by methods well known in the art, such as by reaction with methanesulfonyl chloride in a tertiary amine base.

The mesylate (or sulfonate) of formula ctxxrv is then selectively hydrolyzed to produce the phenol derivative of CLX XV. Protected R111 or M
Selective hydrolysis of the R28 silyl ether group in the presence of the 6-hydroxyl group is accomplished by the use of tetra-n-butylammonium fluoride by the methods described above, well known in the art and described above. Next, the phenol derivative of formula ctxxv is cyclized to give 2CLXX
This produces compounds of VI. Cyclization is most conveniently carried out by treatment of a compound of formula Conveniently used in organic solvents.

The cyclized compound of CLXXVI is then converted to a compound of formula ctxxv,n by ω-carboxyalkylation. Methods well known in the art, such as methods for preparing 3,7-interphenylene-PGFα compounds and corresponding phenolic intermediates, are used. , formula CL
Reaction of compound XXVI with sodium hydride and -z
This is carried out by adding into the molecule an alkyl bromoalkanoate corresponding to the 4-coor+ group. Compounds of formula ctx x v m can then be deprotected, i.e. by hydrolysis of the protecting group under mild acidic conditions C1, and subsequent conversion to various other c-1 derivatives by the methods described below. Manufactured.

Reaction Scheme U provides a convenient method for converting compounds of Formula XI, which are Y+ or trans-CII=CI+-, which are the Formula CCX provide a method. This conversion is accomplished by ozonolysis by methods otherwise well known in the art.

Intermediates of formula ccxxn can then be prepared by the method described above i.e. formula cc
Reaction of compounds of xxm with a suitable Wittig reagent followed by reduction and hydrolysis conveniently converts them to various products of formula XI (compounds of formula ccxx+n of reaction scheme U). Accordingly, by the method described in Reaction Scheme U, the C-12 open chain of various 2-CCXXI compounds is conveniently modified with the 2-CCX X II aldehyde intermediates of the present invention.

As mentioned above, the methods described here are variously applicable to carboxylic acids (where χ1 is 100OR+ and L is hydrogen) or esters or primary alcohols (where x is -0112). lead to.

When an alkyl ester is obtained and an acid is desired, saponification procedures as well known in the art for PGF type compounds are used.

When an acid is prepared and an alkyl, cycloalkyl or aralkyl ester is desired, esterification by reaction between the acid and a suitable diazo hydrocarbon is advantageously carried out. For example, when diazomethane is used, a methyl ester is prepared. .

For example diazoethane, diazobutane and 1-diazo-2
Similar use of -ethylhexane and diazodecane gives ethyl, butyl and 2-ethylhexyl and decyl esters, respectively. Similarly, diazocyclohexadi and phenyldiazomethane produce cyclohexyl and benzyl esters, respectively.

Esterification with diazo hydrocarbons is carried out by mixing a solution of the diazo hydrocarbon in a suitable inert solvent, preferably diethyl needle, with the acid reactant, advantageously in the same or different inert diluent. It is done. After completion of the esterification reaction, the solvent is radically removed and the ester, if desired, purified by conventional methods, preferably chromatography. Contacting the acid reactant with the diazo hydrocarbon is preferably no longer than necessary to achieve the desired esterification to avoid undesirable molecular changes, preferably from about 1 to about 10 minutes.

Diazo hydrocarbons are well known in the art or can be prepared by methods well known in the art6, such as by "organic reactions".
Organic Reactions) J. Joan Imary & Sons Incorporated,
New York, N,'/, vol. 8, pp. 389-394 (1
954).

Another method for alkyl, cycloalkyl or aralkyl esterification of the carboxy moiety of acid compounds is! It consists of converting the two free acids into the corresponding substituted ammonium salts and then interreacting the radicals with alkyl iodides. Examples of suitable iodides are methyl iodide, ethyl tetraiodide, butyl iodide, isobutyl iodide, tert-butyl iodide, cyclophyllobyl iodide, cyclopentyl iodide, benzyl iodide, phenethyl iodide, and the like.

[Reference Examples and Example 1 The present invention will be more fully understood by the following Examples.

Reference Example 19-deoxy-2°,9α-methane-3oxa-4,5,6-trinor-3,7-(1°,3“-interphenylene)-PGF, (Formula XI: Xl is C0
0II, R2o, R21, R23 and R24 are all hydrogen, Z.

is -el12- R, □ is β-hydrogen, R9 is hydroxy, Yl is trans-C++=CH1 is α-011:
β-H1[1 is α-H:β-H1 and R7 is n-butyl. ) and its corresponding methyl ester (X, is -COOCH, Te) See reaction route P 6 A, methylphenyl-N-methylsulfoximino (3,
A solution of 39 g> in dry tetrahydrofuran (60+ nl) was alternately degassed and flushed with nitrogen to -78
Cooled to 78 °C and treated with 2.8 M methylmagnesium chloride (7,16) for 7 min. The reaction mixture, stirred for 1 minute, was cooled to -78°C and dissolved in 35 ml of dry tetrahydrofuran.
Oxa-1,2,4,5,6-pentanol-3,7-inter nl-phenylene-PGE, 3-(tert-butyldimethylsilyl ether), 11.15-bis(tetrahydropyranyl ether (6,05g) ,
Treated with a solution of a compound of formula C1XXI. The resulting mixture was stirred for 1 h while increasing the temperature from -78 °C to 0 °C, and then stirred for 1 h at 0 °C. The reaction mixture was then diluted with brine (170011) and diluted with diethyl Extracted with ether. The ether extract was then dissolved in brine (170 ml), 0.5 M aqueous potassium bisulfate solution (170 ml), and saturated aqueous carbonate/sodium solution (170 ml).
170+nl) and brine (170ml), dried over magnesium sulfate, filtered and washed with 9[(
N-methyl)-phenylsulfoximinomethyl]-3-
Oxa-1,2,4,5,6-pentanol-3.7-isita-nl-phenyle>-PGF, , 3-(tert-butyldimethylsilyl ether), 1115-bis(tetrahydropyranyl ether) yellow oil 8 ．． It was concentrated to Og. 9- in 150 ml of tetrahydrofuran
[(N-,methyl)-phenylsul; l: ximinomethyl-3-oxa-1,2,4,5,6-pentanol-3.7-inter m-phenylene-PGF,
3- (tert-butyldimethylsilyl ether), 1
1.15-bis(tetrahydropyranyl ether)
(8.0 g) of degassed solution was cooled to 0°C and 50%
j! il:Fi/' water (45 ml) and then
Treated with aluminum amalgam under nitrogen. (
Aluminum Amarcum is 8. OOg of 20 meshes of aluminum in 170 ml of diethyl ether, 3
40 +nl methanol, 8.0 in 275ml water
3gcf) mercury chloride, 170ml methanol and 17
Prepared by washing with 0 ool diethyl ether. ) The resulting black suspension was stirred for 1.75 hours, during which time the reaction temperature was slowly raised from 0 to 15°C, then cooled to 0' and treated with ethyl acetate (210 ml), The mixture was further stirred at 0°C for 30 minutes. The suspension was filtered through diatomaceous earth and the filter cake was washed with ethyl acetate.

-The combined P solution is then mixed with salt water (3 (to ml)) -
Washed with 0.5 M aqueous potassium bisulfate solution (300 ml), saturated aqueous solution of sodium hydrogen carbonate (300 rnl) and brine (300 ml), dried, passed through and the crude formula ct, xxn compound, 9-deoxy -9~methylene=3-oxa-1,2,4,5,8-pentanol-3,7-inter m-phenylene-PGF,
3- (tert-butyldimethylsilyl ether), 1
1.15-Bis(tetrahydropyranyl ether) was condensed to 6.03 g of yellow oil. The crude product was combined with that from the repeat production to give 10.1 g of 2CLX
IT product and send it to Skellysolve B (SSB)
, isomers) on silica gel eluting with 5% ethyl acetate in hexane) yielded 0.93 g.
9-deoxy-9-methylene-3-oxa-1,2,
4,5,6-pentanol-3,7-inter-m-phenylene-PGF, 3-(tert-butyldimethylsilyl ether), and 11.15-bis(tetrahydropyranyl ether) were produced. NHR absorption is 4.52~
It was observed at 5.12 and 6.53-7.30δ. Infrared absorption was observed at 1600 and 1655(2)-1. Silica gel TLC Rf was 0.39 in 10% ethyl acetate in hexanes.

B, 9-deoxy-9-methylene-3-oxa-1,2,4,5,6-pentanol-3 which is the reaction product of part A
．． 7-inter m-phenylene-PGF, 3-
(Tertiary butyldimethylsilyl ether), 11゜15-
Bis(tetrahydropyranyl ether) (1.33g)
A degassed solution of p.p. in dry tetrahydrofuran (70 ml) was cooled to OoC and diluted with 0.5 M 9 under nitrogen.
-5 with borabicyclo[3,3,1]nonane (14 ml)
The dropwise treatment was carried out over a period of minutes. Colorless solution at 0° 4,
Stirred for 5 hours and treated with 30% peracid (arsenic (6 ml) and its lit N potassium hydroxide (6 ml). The resulting suspension was stirred at 0 °C for 30 min at 4°C, and Stirred for 75 minutes while warming to room temperature. The reaction mixture was transferred to a separatory funnel and diluted with brine (300nol) and ethyl acetate (300ml). The layers were separated and the aqueous layer was washed with ethyl acetate (600ml). The organic extract was washed with brine (6 rnl), dried, filtered and the product of formula ct, xxm as a colorless oil, 9)
-deoxy-9α-(hydroxymethyl)-3-oxa-1,2,4,5,6-hentanol-3,7-interrn-phenylene PGF, , 3-(tert-butyldimethylsilyl ether), 11 .15-bis-(tetrahydropyranyl ether) (3.3 g) was condensed by 4. The crude product of formula CLX ,2,
4,5,6-pentanol-3,7-inter m-phenylene-PGF.

3-(tert-butyldimethylsilyl ether), 11
15-bis(tetrahydropyranyl ether) was produced as a colorless oil. NHR absorption is 4.73.5.12
〜5.70.6.52〜7.23δ at lI! It was noticed. Infrared absorption is 3480 and 1670(2)-1
It was observed in

Silica gel TLC Rf was 0.21 in 35% ethyl acetate in hexanes.

9-deoxy-9α-hydroxymethyl-3-oxa-1,2,4,56-pentanol-3.7-inter m-phenylene PGF, which is the reaction product of parts C and B;
3-(tert-butyldimethylsilyl ether), 11
．． 15-bis(tetrahydropyranyl ether) <
A degassed solution of 2.01 g) in dry methylene chloride (45 ml) was cooled to -5°C under nitrogen and treated with triethylamine (0.72 rn) then methanesulfonyl chloride (0.76011). The resulting solution was stirred at -5°C for 5 minutes, then the reaction solution stirred for 75 minutes while warming to room temperature was poured onto water, and the resulting mixture was swirled for 2-3 minutes, then Transferred to a separatory funnel and partitioned between diethyl ether and brine.
The layers were separated and the aqueous layer was extracted with ether (400a+I). The organic layer was washed with brine (200 ml) and saturated aqueous sodium bicarbonate (400 ml), dried, filtered, and the product of formula CIXXIV, 9
-deoxy-9α-mesyloxymethyl-3-oxa-1
,2,4,5,6-pentanol-3,7-interm-
7-enylene-PGF, 3-(tert-butyldimethylsilyl ether), 11.15-bis(tetrahydropyranyl ether) was concentrated to a colorless oil. The product (2,69 g) was chromatographed on silica gel (185 g), eluting with 25% ethyl acetate in Sugelisolve B, yielding 1.99 g of 9-deoxy-9α-acyloxymethyl-3- Oxa-1,2゜4
．． 5.6-pentanol-3.7-inter m-phenylene-PGFI, 3-(tert-butyldimethylsilyl), 11.15-bis(tetrahydropyranyl ether) is produced. The absorption of NHR is 2.95.4
．． 70.5.20-5.70 and 6,52-7.22
observed at δ. Silica gel TLC I? f is
It was 0.30 in 35% ethyl acetate in hexane.

9-deoxy-9α-acyloxymethyl-3-oxa-1,2,4,56-pentanol-3,7-inter m-phenylene PGF, which is the reaction product of parts D and C;
3- (tert-butyldimethylsilyl ether),
11.15-bis(tetrahydropyranyl ether)
<0.971 g> of dry tetrahydrofuran (
The degassed solution in 35(III) was cooled to 0°C and treated with 0.75M tetrabutylammonium fluoride (2.6ml) under nitrogen. The resulting amber solution was heated at 0-5°C for 2 Stir for .5 hours and add ethyl acetate (
One layer was separated, partitioned between 150 ml) and brine (150 ml), and the aqueous layer was dissolved in ethyl acetate (300 ml).
Extracted with. The W4 layer was then washed with 0.5 M aqueous ammonium chloride (1501111), saturated aqueous sodium bicarbonate (300 (Ill)) and brine (150 ml), dried, filtered and condensed to yield 0.82 g.
9-deoxy-9α-, a product of formula ctxxv of
Acyloxymethyl-3-oxa-1,2,4,5゜6-
Pentanol-3.7-inter m-phenylene PGFI
, gave 11.15-bis(tetrahydropyranyl ether). Infrared absorption was observed at 3330c111-'. Silica gel TLC Rf was 0.37 in 5025 ethyl acetate in hexanes.

9-deoxy-9α-acyloxymethyl-3-oxa-1,2,4,5°6-pentanol-3,7-inter m-phenylene PGF, which is the reaction product of parts E and D;
, 11.15-Bis(tetrahydropyranyl ether) (0,82 g) was cooled to -40 °C under argon and 57% sodium hydride (0,67 g)
The resulting suspension was stirred at -40°C for 40 minutes and then at 0°C for 15 minutes. The suspension was stirred for a further 20 minutes while warming to room temperature and then refluxed for '2.
The reaction, stirred for 5 hours, was then cooled to 10°C, diluted with water-cooled brine (200ml), and diluted with ethyl acetate (45ml).
0+nl). The ethyl acetate extract was then diluted with brine (
300 ml), dried, passed through and concentrated to yield 0.72 g of crude product of formula CLXXVI. The product was chromatographed on silica gel (175 g) in 25% ethyl acetate in Sugelisolve B to yield 0.49 g of 9-deoxy-2゛,9α-methano-
3-Oxa-1,2,4,5,6-pentanol3.7
- (1°, 3'-interphenylene)-PGF,
, 11.15-bis-(tetrahydropyranyl ether) was produced. NHR absorption is 4.77.5.32
~6.03 and 6.52-7.22δ. Infrared absorption was observed at 3340 and 1670C11-'. Silica gel TLC Rf was 0.56 in 35% ethyl acetate in hexane.

F, the reaction product of part E, 9-deoxy-2°,9
α-Methano-3-oxa-1,2,4,5,6-pentanol-3.7-(1',3'-interphenylene>PGFI, 11.15-bis(tetrahydropyranyl ether) (0,47g) , dried grime (
15 ml) of degassed '! The solution was cooled to 0°C and treated under nitrogen with methyl bromoacetate (0,26 ml) followed by a 57% suspension of sodium hydride (0,136 g).
Processed with.

After vigorous foaming, a white precipitate formed. The resulting suspension was stirred at 0-5°C for 2.5 hours and then soaked in water-cooled brine (200
ml) and extracted with ethyl acetate (450 ml). The ethyl acetate extract was washed with brine (300 ml), dried over magnesium sulfate, filtered, and left in a pale yellow oil.
°, 9α-methane-3-oxa-4°5.6-dolinol-3,7- (1°I3°-interphenylene) -
Concentrated to PGF, methyl ester, 11.15-bis(tetrahydropyranyl ether) (0.62 g). Infrared absorption is 1765 and 1740 (2)
-1 was observed.

9-deoxy-2”, 9α, which is a reaction product of G and F parts
-methane-3-oxa-4,5,6-trinor-3,7
-(1°,3°-interphenylene) PGF methyl ester, 11.15-bis(te)helahydrobilanyl ether) (0,62 g), acetic acid (15 ml)
>, water (7,5+111) and tetrahydrofuran (5
The solution in water-cooled brine (200 cal
) was diluted with The resulting ylA suspension was diluted with ethyl acetate (40
0rol) and the organic extract was extracted with brine (400
[111), jM aqueous sodium bicarbonate solution (60
The ethyl acetate extract, washed with 0+ml)' and brine (200ml), was then dried over magnesium sulfate, filtered and concentrated to give 0.44g of a yellow oil. .

This crude product was dissolved in 50% ethyl acetate in Sugelisolve.
Chromatography on silica gel (<60 g) yielded 0.37 g of raw rlj, which crystallized to 0.216 g of the title product. 9-deoxy-2°,9α-methano-3-oxa-4,5,6-trinor-3,7-(1′,3′-interphenylene)
PGFI, produced a methyl ester. Melting point range is 8
The temperature was 2-84°C. N14R absorption is 3.77.4.
62. .

Observed at 5.42-5.63 and 6.53-7.25δ.

Infrared absorption is 3520.3400, and 1735■-
It was observed in I. Silica gel TLC Rf was 0.30 with 35% acetone in methylene chloride.

The reaction product of part G, 9-deoxy-2°19α-methane-3-oxa-4,5°6, in 5% potassium hydroxide in H,9:1 methanol-water (5,5ml) -Drinol-3,7- (1',3'-interphenylene
A solution of -PGF, , methyl ester (0.15 g) was stirred at O<0>C under nitrogen. The solution initially became cloudy and a precipitate formed within 5 min. The reaction was then stirred for 1 h at 0 °C, diluted with water-cold brine (90(01), acidified with IN HCl, and Extracted with ethyl (180 ml). The ethyl acetate extract was then washed with brine (270 ml), dried over magnesium sulphate and I
A condensation produced a waxy semisolid (0,131 g), which was crystallized to give 0.105 g of the title product, 9-deoxy-2°,9α-methano-3- Oxa-4,5,6-1-linol-3,7-(1°,3°-interphenylene)-PGFI was produced. The melting point range was 131-133°C.

N HI+ absorption is 4.68.5.48-5.72.6
1flK was observed between 68° and 7.22°. Infrared absorption was observed at 3460.3280.1735.1720 and 1700(to)-1.

■ The dosage at which the title compounds should be administered to obtain their effects; primarily antiplatelet aggregation or blood pressure lowering, will vary depending on the potency of the particular compound currently under investigation, and will be administered orally. Sometimes the compound is present in humans at a dosage of about 0.05 to about 50 μ/kg, preferably about 0.1
The compound, 9-deoxy-2',9α-methano, given orally to mice at a dose of 1 ■/'kIr, will show the desired effect at an oral dose of ~5 ■/'ht. -3-oxa-4,5,6-drino-3,7- (1
',3'-interphenylene) -PGF + ,
Methyl ester reduced blood pressure by 44u+llu.

After 52 minutes the blood pressure was still 14- lower. Intravenous doses for the desired effect range from about 1 to about 500 in humans.
nQ/'ktr/'min, preferably from about 10 to about 100 n
g7 kg/'min.

Table 9-deoxy-2゛, 9α-methano-3-oxa-4,5,6,13,14,15,10,17,18
,19,20-undecanol-3.7-(1',3'-
interphenylene)-12-formyl-PGF.

Methyl ester (formula CCX X ■: L is -C00
C113, Z is -CIl□-R2゜, R21, and R
23 is hydrogen, L2 is β-hydrogen, and R18 is tetrahydropyran-2-yl-oxy) See reaction frame v@U.

50 ml of the reaction product of Part F of Reference Example 1 of 0.72 g
Ozone was bubbled through the anhydrous methanol solution at −78° C. for 5 minutes. Oxygen was then bubbled through the resulting solution for 5 minutes and the solution was treated with 16 ml of dimethyl sulfide. After standing for 16 hours at 0 °C under a nitrogen atmosphere and 2 hours at room temperature, the solution was
diluted with 100 ml ethyl acetate, 100 ml brine, 10
0 ml of saturated aqueous sodium bicarbonate solution and 100 ml
brine, dried over anhydrous sodium sulfate, condensed under reduced pressure, and chromatographed on 175 g of silica gel, eluting with 35% ethyl acetate in hexane, to give the title product of 367. A product formed as a colorless oil. NHR absorption (CDCJ, ) is 1
．． 0~3.0.3.1~4.5.3.63. -6.45
~7.34, and 9,77δ. The mass spectrum showed peaks at 388 and 304. Rf of silica gel TLC is 25% in hexane
and 0.19 and 0.22 in 30% ethyl acetate.

Reference example 29-deoxy-2°,9α-methano-20-methyl-3-oxa-4,5,6-dolinol-3,7-
(1°, 3°-interphenylene)-PGFI (formula
I: Xl, Z4, R8, R2°, 1121, R22, R
2), R24°Y+, H+, and Ll are as defined in the Reference Examples and R7 is n-pentyl), the methyl ester thereof <1. is -COOC11),
its 15-epimer (H, is α-H:β-OH) and the 15-epima methyl ester (Ml is α-II:
β −0]1, and Z is -COOCL) See reaction scheme U.

A. 56 kg of a 57% dispersion of sodium hydride in mineral oil and 28 kg of a suspension in 4 ml of tetrahydrofuran in 4 ml of tetrahydrofuran under a nitrogen atmosphere at 0 °C.
of dimethyl-2-octylphosphonate, stirred for 5 minutes at 0°C, stirred for 1 hour at room temperature,
Cool to 0.39 g of the title product of the example and 4.
ml of tetrahydrofuran at room temperature.
Stir for 7'2 hours, cool to 0°C, add to 40 ml of ethyl acetate containing 5-6 drops of acetic acid, extract with 120 ml of ethyl acetate, wash with 30 ml of saturated aqueous sodium hydrogen carbonate solution, brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield an oil.
and 6 while eluting with 25% ethyl acetate in hexane.
Chromatography on 0 g of silica gel yields 0
．． 42 g of 9.15-dideoxy-15- as a colorless oil
Geto2"19α-methano-20-methyl-4,5,6
-trinor 3.7 <1°, 3°, -interphenylene) -PGF.

The methyl ester, 11-tel-rahydropyranyl ether, was produced. NHR absorption is 0.89.1.05 ~
3.0.3.5-4.37.4,62, and 5.97・
Observed at ~7.30δ. The mass spectrum is
Peaks were shown at 414.396.323.311 and 301. Silica gel TLC Rf was 0.26 in 25% ethyl acetate in hexanes.

8. A degassed solution of 42 parts of sodium hydride and 4 ml of anhydrous methanol is mixed with 391 parts of part A in 0.3 ml of methylene chloride and 3 ml of methanol at -30°C under nitrogen atmosphere. treated with a solution of the title reaction product,
Stir for 117'2 hours at -30°C, quenched by careful addition of 0.2 ml of glacial acetic acid, dilute with 70 ml of brine, extract with 210 ml of ethyl acetate, and add 70 ml of saturated aqueous sodium bicarbonate solution. Washed with 70 ml of brine, dried over anhydrous sodium sulfate, condensed under reduced pressure to yield 0.42 g of a colorless oil, and eluted with 40% ethyl acetate in hexane. Chromatography on 60 g of silica gel yields 0.36 g
gave an epimer mixture of C-15 alcohols. Silica gel TLC Rf was 0.20 in 40% ethyl acetate in hexanes.

C, a solution of the reaction product of Part B above in 3 ml of tetrahydrofuran, 4.5 ml of water, and 9 ml of acetic acid is heated to 45° C. under nitrogen atmosphere for 2.5 hours, cooled, Dilute with 100 ml of brine, extract with 200 ml of ethyl acetate, wash with 100 ml of brine,
00 ml of saturated aqueous sodium bicarbonate solution and 100 ml of saturated aqueous sodium bicarbonate solution
Washed with 1 ml of brine, dried over anhydrous sodium sulfate,
Concentration under reduced pressure to a yellow oil and chromatography on 60 g of silica gel with 20% ethyl acetate in methylene chloride at i8 gF yielded 96 μ of 9-deoxy-2′,9α-methano- 20-Methyl-3-oxa-4,5,6-trinor-3,7-(1,3-interphenylene)-15-shrimp-PGF, the methyl ester as a colorless oil, and 159 9-deoxy -2゛,9α-methano-20-methyl-3-oxa-4
,5,6-trinor-3,7-(1,3-interphenylene)-PGF, , methyl ester was produced as a white solid. Recrystallization of the 15α-hydroxy compound from hexane in mature diethyl ether yields 140
gave a white solid. The melting point range was 79-82°C. For the title product methyl nisder, the NHR absorption is from 0.92.1,08 to 3.0.3.38 to 4.5
．． 4.64.5.33-5,70, and 6.5-7.4
It was observed in The mass spectrum of the trimethylsilyl derivative showed a high resolution peak at 560.3375. Silica gel TLC Rf was 0.19 in 20% ethyl acetate in methylene chloride and 0.131 in 20% hexane in ethyl acetate. For the 15-epi compound, the NHR absorption (C0CfJs) is 0.89.1.07-3.0, 3.7-4.33.
4.63.5.5-5.8 and 6.55-7.37δ
It was observed in

Infrared absorption is 3360.1765.1750.173
5.1605.1585.1470.1440.120
5.1120.1080.970, and 770(2)-
l in 1! 51 was detected. The mass spectrum of the trimethylsilyl derivative showed a high resolution peak at 560.3385. The Rf of silica gel TLC is 0.35 in 20% acetone and methylene chloride and 2
It was 0.45 in 0% hexane and ethyl acetate.

D. Following the method of Part H of Reference Example 1, 0 parts of the 15α-monohydroxy title product (94■) was converted to the title free acid 9-deoxy-2°,9α-methano- as 81■ of a white solid. 20-Methyl-3-oxa-4,5゜6-dolinol-3,7-(1,3-interphenylene) -PG
It was converted to F. The melting point range was 144-146°C. N141? Absorption (CD, 000 mouths) is 0.
8.1°05~2.9.3.2~4.5.4.65.5
．． 38-556, and 6.6-7.2 δ and rI
f4 was detected. The mass spectrum of the tonomethylsilyl derivative showed a high resolution peak at f318.357G. The Rf of silica gel TLC is 0 in A-IX solvent system.
, 14.

E. Further, according to the method of Part H of Reference Example, the 15-shrimp title product (93) of Part C was mixed with 72 parts of a white solid.9
-deoxy-2',9α-methano-20-methyl-3-
Oxa-4,5,6-1 ~ Linol-3.7- (1,3
-interphenylene)-15 to shrimp-PGF. The melting point range was 105-108'C.

It HR absorption (CD3COCD, ') is 0.90
．． 1.05~2.9.3.2~4.3.4.7L 5.
0 to 5.84, and 6.5 to 7.34 δ. The Rf of silica gel TLC was 0.19 in the 8-IX solvent system.

According to the method of Examples and Reference Example 2, C-12@ according to the method of Reaction Route U in place of each of the various 2XI compounds
The chain was replaced.

Structure 1 day.

formula CLXXI'/η\ et al. ↓ Reaction route U II 11 M6L engineering ↓ CXXI CXXm

Claims (1)

[Claims] 1. Carbacycline intermediate of the formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ VIII [In the formula, R_1_3 is -OR_1_0 (here, R_1_0 is a protecting group such as tetrahydropyranyl), R_2_0 , R_2_1, R_2_2, R_2_3 and R_2_4 are all hydrogen, R_2_2 is either α-hydrogen or β-hydrogen, R_3_3 is -CHO, and X_1 is -COOR_1 (where R_1 is (C_1-
C_1_2) is alkyl), and Z_4 is -CH_2-. ] or pharmacologically acceptable salts thereof.